Mechanism for Production of Pharmacologically Active Metabolite of CS-747, A New Anti-Platelet Agent

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Abstract
CS-747, a prodrug-type thienopyridine anti-platelet agent, was converted to pharmacologically active metabolites in vitro in isolated rat hepatocytes. The active metabolites had a free sulfhydryl group, and were associated with 2 asymmetric carbons. Of 4 optical isomers of the active metabolites, one optical isomer showed a high activity in inhibiting the platelet aggregation. Other metabolites of CS-747 without having free sulfhydryl group, produced by rat hepatocytes in vitro, were pharmacologically inactive. The active metabolites were also detectable in plasma after oral administration of CS-747 to rats and dogs. In the plasma of rats and dogs after administration of 14C-CS-747, disulfide-type cysteine conjugates of the active metabolites were detected as the most major metabolite. The cysteine conjugates of the active metabolites were not pharmacologically active in vitro while these were active in vivo after intravenous administration to rats, suggesting their conversion to the active metabolite after disulfide reduction. The activity to produce the active metabolite in 9000g supernatant fraction of rat liver was NADPH-dependent and inducible by phenobarbital, suggesting an involvement of cytochrome P450. Experiments using various isoforms of expressed human liver cytochrome P450 indicated that CYP3A4 and CYP2B6 are involved in this metabolic activation.

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